Malaria, caused by Plasmodium parasites, is one of the top infectious killers of children worldwide. Natural immunity is thought to involve protective antibody, but long-lasting antibody responses develop only after many repeated exposures, leaving children vulnerable. It has been proposed that dysfunctional B cell responses may in part explain this slow acquisition of humoral immunity. Consistent with this, numerous studies have characterized an unusual population of B cells, called atypical memory B cells (atMBCs), that expands in humans with chronic Plasmodium exposure as well as in other chronic conditions. Defined by the absence of classical MBC markers CD21 and CD27, atMBCs exhibit poor proliferation and antibody secretion ex vivo, raising speculation that they are dysfunctional. However, their physiological role in vivo remains a mystery, largely due to the lack of an appropriate model system: it has been difficult to identify an analogous population in the mouse, which lacks memory B cell markers equivalent to human CD21 and CD27. Recently a putative inhibitory receptor, Fc Receptor-Like 5 (FCRL5), was shown to be upregulated on atMBCs from Plasmodium- exposed humans, and its expression correlates strongly with poor antibody secretion ex vivo. The homologous mouse marker FCRL5 has previously been considered a marker of innate-like B cells, but this proposal now demonstrates that a subset of antigen-specific, non-innate FCRL5+ mouse B cells inducibly expands during infection with P. chabaudi. Extensive transcriptional and phenotypic analysis has revealed strong similarities between these induced FCRL5+ B cells and atMBCs from Plasmodium-exposed humans, including association with class-switching; a transcriptional landscape suggestive of immune suppression; and expression of the master transcription factor T-BET. Based on substantial preliminary data, this research proposal seeks to determine whether Plasmodium-induced murine FCRL5+ B cells are indeed analogous to human atMBCs and, further, to test the hypothesis that this subset is defective for antibody secretion and immune protection in vivo. The specific aims are to (1) assess the physiological functions of induced FCRL5+ B cells both ex vivo and in vivo, and (2) identify factors that modulate the expansion of induced FCRL5+ B cells during P. chabaudi infection. The proposal employs several innovative tools, including recently created tetramers that allow tracking of small numbers of antigen-specific B cells and a novel model of persistent P. chabaudi infection that improves upon existing models of acute infection in recapitulating the human immune response to chronic malaria. This project has outstanding potential to reveal the regulation and function of a poorly understood B cell subset that arises in many chronic disease settings, from malaria to HIV to lupus. Beyond yielding insight into antimalarial immunity, it will establish a framework with which to analyze B cell dysfunction in diverse diseases. Finally, this important work will inform future therapeutic and vaccine strategies aimed at modulating or preventing development of atMBCs in chronic disease.